PB1916: SOMATIC MUTATIONS ASSOCIATED WITH MYELODYSPLASTIC SYNDROME IN RUSSIAN PATIENTS
Authors: A. Kohno, B. Biderman, A. Sudarikov, S. Treglazova, A. Abdullaev, S. Kulikov, Y. Chabaeva, V. Dvirnyk, T. Obukhova, V. Troitskaya, E. Parovichnikova
Journal: HemaSphere (2022)

Background: Myelodysplastic syndrome (MDS) is characterized by the presence of clonal hematopoiesis, with genetic mutations detected in 90% of cases. Their significance in the pathogenesis, clinical picture, and prognosis of the disease has been actively studied in recent years. Aims: To study somatic mutations and their prognostic significance in Russian patients with MDS. Methods: The study included 48 patients with MDS, aged 19-80 years (Me-50), 25M/23F. According to WHO classification (2017), the variants of the disease were identified as MDS with ringed sideroblasts - 7 (14.6%), MDS with multilinear dysplasia - 16 (33.3%), MDS with 5q- - 8 (16.7%), MDS with an excess of blasts - 17 (35.4%). Cytogenetic analysis revealed normal karyotype in 18 cases (37.5%), an abnormal karyotype in 29 (60.4%), and in 1 case (2.1%) no mitosis was observed. A custom panel (Qiagen, USA) was designed for targeted next-generation sequencing (NGS) of SF3B1, U2AF1, SRSF2, ZRSR2, DNMT3A, TP53, ASXL1, RUNX1, TET2, NRAS, GATA2, and EZH2 genes. The results were analyzed using the open-source QIAseq Targeted DNA Variant Calling software (Qiagen, USA). Only somatic mutations were included in the final analysis (based on the VAF value). Results: In 34 (70.8%) MDS patients somatic mutations were detected. In 17 of 34 (50.0%) mutations were found in 2 or more genes. The distribution by frequency of detection was as follows: ASXL1 - 12 (25.0%), RUNX1 - 10 (20.8%), DNMT3A - 8 (16.7%), TET2 - 8 (16.7%), SRSF2 - 6 (12.5%), SF3B1 - 5 (10.4%), U2AF1 - 4 (10.4%), ZRSR2 - 3 (6.3%), TP53 - 2 (4.2%), NRAS - 2 (4.2%), GATA2 - 2 (4.2%), EZH2 - 0. For 18 patients with normal karyotype, somatic mutations were detected in 13 cases (72.2%) cases. These were mutations in ASXL1 - 3 (23.1%), RUNX1 - 4 (30.8%), DNMT3A - 1 (7.7%), TET2 - 2 (15.4%), SRSF2 - 3 (23.1%), SF3B1 - 4 (30.8%), U2AF1 - 2(15.4%), ZRSR2 - 1(7.7%), TP53 - 1(7.7%), and NRAS - 1 (5.0%) genes. Mutations in a single gene were detected in 8 patients (61.5%) patients; double mutations - in 3 patients (23.1%); 3 or more mutations were found in 2 cases (15.4%). Of the above mentioned, only SF3B1 gene mutations can be associated with a favorable prognosis. When analyzing the mutational profile in MDS patients with 5q- (n=8), mutations were detected in 50.0% of cases and occure in genes: DNMT3A - 3 (37.5%), TET2 - 1 (12.5%), ASXL1 - 2 (25.0%), TP53 - 0. In 2 cases with a combination of mutations in the DNMT3A+TET2 and DNMT3A+ASXL1 genes, progression to AML was noted. In a unifactorial analysis, for all MDS patients progression to AML was significantly associated with mutations in the RUNX1 (p=0.001) and SRSF2 (p=0.0026) genes. While worst survival was associated with mutations in the RUNX1 (p=0.0012), SRSF2 (p= 0.0101) and U2AF1 (p=0.0276). Summary/Conclusion: The data obtained on 48 patients with MDS demonstrate a high frequency of somatic mutations (70.8%), including those detected in cases with normal karyotype (72.2%). An unfavorable prognosis was associated with RUNX1, SRSF2, and U2AF1 gene mutations. Extending of a patient sample is required to assess the predictive value of other somatic mutations in MDS.